The FDA has approved pirtobrutinib for the treatment of chronic lymphocytic leukemia (CLL) and small

On December 3, 2025, the U.S. Food and Drug Administration (FDA) granted full approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously received treatment with a covalent BTK inhibitor. In 2023, the FDA had approved pirtobrutinib under the accelerated approval pathway for the treatment of adult patients with CLL/SLL who had previously received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

Efficacy and Safety

Efficacy was evaluated based on the BRUIN-CLL-321 study (NCT04666038), a randomized, open-label, active-controlled trial. A total of 238 previously treated patients with CLL/SLL were randomly enrolled in the trial, and all had received a covalent BTK inhibitor in their prior treatment. Patients who had previously received treatment with a non-covalent BTK inhibitor were not allowed to enroll. Patients were randomly assigned in a 1:1 ratio to receive either pirtobrutinib treatment, or investigator’s choice of idelalisib in combination with a rituximab product (IR) or bendamustine in combination with a rituximab product (BR). For patients in the investigator’s choice treatment group, crossover to single-agent JAYPIRCA was permitted upon confirmation of disease progression.

The primary efficacy endpoint was progression-free survival (PFS), assessed by an independent review committee in accordance with the 2018 iwCLL criteria. The median PFS was 11.2 months (95% CI: 9.5, 11.4) in the pirtobrutinib group, compared with 8.7 months (95% CI: 7.2, 10.2) in the investigator’s choice IR/BR group (hazard ratio 0.58 [95% CI: 0.38, 0.89]; p-value 0.0105). Of the 119 patients in the investigator’s choice group, 50 crossed over to receive JAYPIRCA treatment. In an updated analysis with a median follow-up duration of 19.8 months, the hazard ratio for overall survival (OS) was 1.09 (95% CI: 0.68, 1.75).

The prescribing information includes warnings and precautions regarding infection, bleeding, cytopenias, arrhythmias, secondary primary malignancies, hepatotoxicity, and embryo-fetal toxicity.

Recommended Dosage

The recommended dosage of pirtobrutinib is 200 mg, administered orally once daily, until disease progression or the occurrence of unacceptable toxicity.

Accelerated Approval Program

An "Assessment Aid" was used in this review. It was voluntarily submitted by the applicant to assist the FDA in conducting the assessment.

Pirtobrutinib previously received orphan drug designation. For a description of the FDA’s accelerated programs, please refer to the industry guidance document: Accelerated Programs for Drugs and Biologics for Serious Conditions.